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2. disease

MPS IVA
Mucopolysaccharidosis type IVA:
Morquio A syndrome
The 1st International Morquio family meeting in LA, USA (Oct. 2003)
Producers:
Morquio families
International Morquio Organization (Carol Ann Foundation)
Dr. S. Tomatsu (Department of Pediatrics, Saint Louis University)
These educational CD slides were kindly co-produced by Morquio families, International
Morquio Organization (IMO), and Dr. Shunji Tomatsu (Department of Pediatrics, Saint
Louis University) to increase the awareness of mucopolysaccharidosis IVA (MPS IVA;
Morquio A syndrome). It provides a short introduction about lysosomal storage
disorders (LSD) and MPS in general, before going into more detail about MPS IVA. We
have tried to cover the whole spectrum of disease, ranging from the most severe MPS
IVA patients to the attenuated form of the disease. The slides included the update basic
research and clinical research. The slides can be used for education to physicians,
families, patients, and local communities.
We would like to thank individual Morquio families for providing the pictures and
acknowledge Dr. Tadao Orii (Department of Pediatrics, Gifu University) and Dr.
William Mackenzie (Department of Pediatric Orthopedics, Alfred I. duPont Hospital for
Children) for contributing the slides and proofreading the slides.
Please contact Mary Smith (President of IMO; www.morquio.com) if you have any
question on this educational CD. IMO has been founded in 1997 by Mary Smith.
This educational CD is translated or under translation into the following languages:
Arabic, French, German, Italian, Japanese, Polish, Portuguese, and Spanish. If you need
educational CD for one of those languages, please ask IMO office.
© 2005 International Morquio Organization
All rights reserved
Images from this slide series may not be used outside of this presentation.
IMO was kindly provided a funding for educational CD by the following companies;
BioMarin, Geznyme, Inotech, Shire. We thank for such a kind contribution on behalf of
Morquio families.
Morquio A Disease
MPS IVA
Introduction to LSDs
Introduction to MPSs
Introduction to MPS IVA
Clinical overview
Clinical presentation - General
Clinical presentation – Organ specific
Genetics of MPS IVA (Morquio A Disease)
Diagnosis and misdiagnoses
Management and treatment
Summary
MPS IVA
Mucopolysaccharidosis
type IVA
Introduction to
LSDs
Lysosomal Storage Disorders
(LSDs)
A group of over 40 genetic disorders
Due to a deficiency of a lysosomal enzyme resulting in
the accumulation of substrate in the cells
Jointly affect an estimated 1:7,700 newborns
Usually displaying progressive disease pattern, with
wide spectrum of symptoms, signs and severity.
normal
affected
LSD subdivision
Sphingolipidoses
Mucopolysaccharidoses
Failure to degrade
Failure to degrade
glycosaminoglycans
glycosphingolipids containing three
Hurler, Hunter, Sanfilippo,
or less carbohydrate residues.
Morquio, Maroteaux-Lamy, Sly
Fabry, Gaucher, ASM deficiency
(Niemann Pick A,B),
Metachromatic Leukodystrophy,
Krabbe,….
Oligosaccharidoses
Others
Failure to degrade oligosaccharides Pompe, Mucolipidosis, Ceroid
lipofuscinosis, …
Fucosidosis, Mannosidosis,
Sialidosis, Galactosialidosis,…
Incidence of LSDs in Europe
Relative diagnostic frequency
(Portugal, 1982-2001)
Relative birth prevalence
(Netherlands, 1970-1996)
Oligosaccharidoses
Others
9.9 %
Others
MPS
26.3 %
19.0 %
MPS
33.1 %
Sphingolipidoses
Sphingolipidoses
60.2 %
45.0 %
Incidence of lysosomal storage disorders (LSDs) in
Australia (1980-1996)
Gaucher
14%
Sandhoff 2%
GM1 Gangliosidosis 2%
Mucolipidosis II/III 2%
Niemann Pick A/B 3%
MPS VI 3%
MPS I
9%
Niemann Pick C
4%
MPS III B
4%
Tay-Sachs
4%
Cystinosis
4%
Metachromatic
Leukodystrophy
8%
MPS IIIA
7%
MPS IV (Morquio)
5%
Pompe
5%
Krabbe
5%
MPS II
6%
Fabry
7%
Incidence of each type of MPS
(number of patients in each bar)
MPS I
100%
44
80%
MPS II
6
4
MPS III
6
6
22 5
MPS IVA
1
15
11
18 2
3
23
3
26
64
46
3
52
22
31
1
38
14
82
51
20
48
6
12
0%
Japan
3
2
5
156
205
20%
MPS VII
10
6
40%
MPS VI
25
75
60%
MPS IVB
North Ireland Netherlands
Portugal
Australia
British
Colombia
Poland
MPS IVA
Introduction to MPSs
Common features among MPS
7 different types divided in subtypes
Progressive, life threatening, multi-systemic diseases
Heterogeneous clinical presentation
Accumulated substrates are glycosaminoglycans (GAG):
Dermatan sulfate
Pattern of accumulation dependent
Heparan sulfate
on the type of MPS
Keratan sulfate
Chondroitine sulfate
Detected by measuring GAGs in the urine
To be confirmed by analysis of specific deficient enzyme
MPS current status
Disorder
Deficient Enzyme
Trait
Chromosome
Storage material
MPS I (Hurler)
α-L-Iduronidase
AR
4p16.3
HS, DS
MPS II (Hunter)
Iduronate-2-sulfatase
XR
Xq28
HS, DS
MPS IIIA (Sanfillipo A)
Heparan-N-sulfatase
AR
17q25.3
HS
MPS IIIB (Sanfillipo B)
α-N-Acetylglucosaminidase
AR
17q21
HS
MPS IIIC (Sanfillipo C)
α-Glucosaminidase
acetyltransferase
AR
-
HS
MPS IIID (Sanfillipo D)
N-Acetylglucosamine 6sulfatase
AR
12q14
HS
MPS IVA (Morquio A)
N-acetylgalactosamine-6sulfate sufatase
AR
16q24.3
KS, C6S
MPS IVB (Morquio B)
β-Galactosidase
AR
3p21.33
KS
MPS VI (Maroteaux-Lamy)
N-Acetylgalactosamine-4sulfatase
AR
5q13.3
DS, C4S
MPS VII (Sly)
β-D-Glucuronidase
AR
7q21-q22
HS, DS, C4, 6S
GAGs
Glycosaminoglycans (GAGs) were previously
named mucopolysaccharides
Biological macromolecules as a proteoglycan
Present in every tissue and organ
Present both extracellular and intracellular
Important component of the connective tissue
and bone matrix
Regulate several cellular events ( e.g. cell
adhesion)
MATRIX EXTRACELLULAR
Cell-Cell adhesions
Intracellular
Attachment Protein
Cell adhesion
molecules
Cytoskeletal
proteins
Plasma
Membrane
Cell
Matrix
Adhesions
Matrix Proteoglycan
Core protein
GAGs
Cell-surface
Proteoglycan core
protein
Multiadhesive
protein
Collagen
Fiber
H2CO S
*Galactose-6 sulfatase
H2CO S
0
H2COH
0
0
0
0
0
0
1
β - Galactosidase
H2CO S
NAc
NAc
H2CO S
H2COH
0
H2COH
0
0
0
N-Acetyl
glucosamine
6-sulfatase
etc
0
Stepwise
degradation of KS
H2CO S
0
0
0
0
etc
2
NAc
H2CO S
NAc
H2COH
0
H2CO S
0
0
0
0
NAc
etc
NAc
3
β – Hexosaminidase A,B
H2CO
H2COH
0
H2CO S
0
0
0
0
NAc
etc
4
H2COH
NAc
H2CO S
0
0
0
etc
NAc
1: MPS IVA
2: MPS IVB
3: MPS IIID
4: Sandhoff
MPS IVA
Introduction to MPS IVA
A disease with many faces and
variations
History for study of MPS IVA
(Morquio syndrome)
1929 - First description of Morquio patients in Uruguay
(Morquio L)
1974 – Identification of defective enzyme in Morquio syndrome
(Matalon R et al.)
1976 – Assay of N-acetylgalactosamine-6-sulfate sulfatase
(GALNS) in Morquio syndrome (Singh J et al)
1991 – Purification of enzyme (Masue M et al., Bielicki J et al.)
1991 - cDNA cloning of GALNS (Tomatsu et al.)
2003 – Establishment of model mouse with Morquio A disease
(Tomatsu et al)
2004 - Development of keratan sulfate assay in Morquio
(Tomatsu et al)
Keratan sulfate (KS)
Inability to degrade KS gives rise to MPS IV,
Morquio syndrome.
KS is present as a style of proteoglycan mainly in
cornea (KS 1 = N-linked) (lumican) and cartilage
aggregated with chondroitin sulfates (KS 2 =Olinked) (aggrecan).
The unique clinical manifestations of this disorder
are attributable to the restricted tissue
distribution of corneas and cartilage, in contrast
to the much wider distribution of dermatan sulfate
and heparan sulfate.
Mucopolysaccharidosis type IV
(MPS IVA)
•
Historically known as Morquio Syndrome
•
Rare (1/200,000 - British Columbia, 1/76,000 Northern Ireland, 1/500,000 - Japan)
•
Progressive accumulation of glycosaminoglycans
(GAGs), mainly Keratan Sulfate (KS) and
Chondroitin-6-sulfate (C6S)
•
Two forms are recognized, type A and type B - MPS
IVA; N-acetylgalactosamine 6-sulfate sulfatase
(GALNS), MPS IVB; β-galactosidase.
•
Autosomal recessive disorder
Aggrecan
Major component of extracellular matrix including
KS (KS 2) and CS.
Large aggregates (molecular size up to 800 MDa)
with hyaluronan and so-called link-protein
Provide a hydrated gel structure of cartilagenous
tissues.
Provide a function to resist compression in cartilage.
Extreme content of negatively charged
polysaccharide chains creating an osmotic
environment that is responsible for the extremely
high osmotic swelling pressure of cartilage.
Prominent feature in joint disease (such as
rheumatoid arthritis and osteoarthritis) by loss of
aggrecan.
Structure of aggrecan
G1
IGD G2
KS rich
CS1
CS2
G3
N-Linked oligosaccharides
EGF
COOH
CRP
Lectin
BB’
A BB’
PTR
COOH
Ig fold PTR
Link protein
KS 2
O-Linked oligosaccharides
CS
Aggrecan
Link Protein
Aggrecan
Collagen
Tension
Hyaluronan
Proteoglycan
Swelling
Collagen
Fibril
Pressure H2O
LUMICAN
•Lumican is a KS (KS 1) proetoglycan most
closely resembling fibromodulin.
•Besides cornea, it can be found from muscle,
cartilaginous tissues, kidney, lung, and
intestine.
•In the cornea, an exact spacing and thickness
of the collagen fibers can be suggested to be
critical for the transparency.
Structure of Lumican
Unit 1
s
s
N
Unit 2
2
5
C
4
Potential N linked oligo site
(Keratan sulfate 1)
Disulfide bonds
Putative β sheet in leucine
rich repeat
s
3
1
Keratan sulfate
s
Unit 3
MOTIFS
LPXXLXXLYLXNNXI
LQXLXLXHNXL
Potential N linked oligo site (High
mannose oligosaccharide)
LXXLDLSFNQL
Keratan sulfate proteoglycan
KS 1 (Cornea)
CH2 OH
CH2 OSO3-
CH2 OSO3-
CH2 OH
CH2 OH
CH2 OSO3-
CH2 OH
Fuc
O
O
O
O
O
CH3
O
O
HN–Ac
HN–Ac
HN–Ac
O
CH
Gal
GlcNAc6S
Gal6S
GlcNAc6S
Gal
GlcNAc
CH2
CH2 OH
NH
N– C-CH2–CH
Man
H O
O
O
C=0
NH
CH2 OH
CH2 OSO3-
CH2 OSO3-
O
O
HN–Ac
O
CH2 OH
CH2 OH
CH2 OSO3-
O
HN–Ac
CH2 OH
O
O
Asn
HN–Ac
O
Man
GlcNAc
GlcNAc
HN–Ac
Linkage Region
Core
Protein
β4
6S
β3
β4
6S
Degradation of KS
β6S
N-acetylgalactosamine-6sulfatase
β4
β3
β4
6S
6S
β3
β-N-Acetylhexosaminidase A
β-
β4
6S
β-Galactosidase
β-
6S
β3
β4
β6S
β4
N-Acetylglucosamine-6sulfatase
β-N-AcetylHexosaminidase A or B
β6S
β-Galactosidase
β-
6S
GALNS deficiency
disrupts the
sequential
breakdown of KS
6S
MPS IVA
Degradation of KS
1
S
H2CO
H2CO
0
H2COH
0
0
0
S
0
0
2
NAc
H2CO
S
0
0
etc
NAc
The deficient diseases corresponding to the numbered
reactions are 1 = MPS IVA; 2 = MPS IVB. In Morquio
syndrome, the degradation of KS is defective because of the
deficiency of either GALNS in MPS IVA or β-galactosidase
in MPS IVB. KS consists of galactose-6-sulfate + GlcNAc6-sulfate
MPS IVA
Clinical overview
Prognosis of MPS IVA
Cervical myelopathy can develop early in patients
with the severe form of Morquio syndrome.
Patients with the severe form may not survive
beyond their twenties or thirties.
Paralysis from the myelopathy, restrictive chest
wall movement, and valvular heart disease all
contribute to their shortened life span.
Length of survival may improve with the
improved comprehensive care available to these
patients today.
MPS IVA – Clinical summary
Systematic bone dysplasia
Wide spectrum of disease
severity
Progressive and debilitating
Severe morbidity and early
mortality
Clinical features of MPS IVA
Deficiency of GALNS
Storage of GAGs in
tissues, especially
cartilage cells
• Short neck and trunk dwarfism
• Fine corneal clouding
• Skeletal dysplasia (cervical spinal
cord compression, pectus carinatum,
genu valgus, kyphoscoliosis)
• Waddling gait with a tendency to fall
• Ligamentous laxity
• Small teeth with thin enamel and
frequent caries formation
• Facial features (coarsening of facies)
• Hearing loss
• Easy fatigue
• Sleep apnea
• Restriction of breathing
• Recurrent infection
SEVERE
ATTENUATED
Disease progression: severe to
attenuated
3 months
12 months
2 years
7 years
Disease progression: severe
1-2 months
1 year
2 years
3 years
6 years
Disease progression: severe
7 years
8 years
11 years
16 years
16 years
3 year
Severe
1 year
2 year
3 year
1 year
1 day
4 year
3 year
6 year
7 year
8 year
9 year
Disease progression: after operation of osteotomy
MPS IVA (10 years old)
Clinical severity
Most severe
Attenuated
Short stature
+++++
+++
+/-
Spinal cord compression
+++++
+++
+/-
Walking disturbance
+++++
+++
+/-
Skeletal malalignment
+++++
+++
+
Dysostosis multiplex
+++++
+++
+/-
Hyperlaxity of joints
+++++
+++
+/-
Obstructive airway disease
+++++
+++
+/-
Hearing loss
++++
++
-
Corneal clouding
+++
+
+/-
Cardiac (valvular) disease
+++
+
-
Morbidity & management - 1
Morbidity
Symptoms
Treatment
Bone Dysplasia
Severe
short stature, abnormal
gait, joint pain, bone
defomities
orthopedic surgeries;
realignment osteotomy,
corrective knee surgery,
hip replacement etc.
Spinal Cord Compression cervical myelopathy,
bowel and bladder
Severe
dysfunction, apnea
spinal bracing, cervical
decompression, cervical
spinal fusion
Joint Disease
Severe
ligamentous laxity
weight control, physical
therapy, wrist splint,
bracing
Obstructive Airways
Severe
sleep apnea, pneumonia,
tracheostomy, high risk
in anesthesia
tonsillectomy and
adenoidectomy,
tracheostomy, CPAP
Morbidity & management - 2
Morbidity
Symptoms
Treatment
Ear problem
Mild to
moderate
Mixed hearing loss; frequent
middle ear infections, deformity
of the ossicles, abnormalities of
the inner ear
ventilating tube, hearing
aid
Eye problem
Mild
corneal clouding; visual
disturbance, photophobia
no definitive treatment,
darkened glasses
Dental problem
Severe
dental caries and tooth fractures
and; abnormally thin enamel
daily oral hygiene,
professional dental
cleaning , sealants
Heart problem
Mild
cardiac dysfunction; coronary
heart disease and valve
thickening
endocarditis prophylaxis,
valve replacement
MPS IVA
Clinical symptom in
MPS IVA
General
Physical appearance
Short trunk dwarfism
Genu valgum (knocked
knee)
Pectus carinutum
(pigeon chest)
Kyphoscoliosis
Hypermobile joints
Fine corneal clouding
Facial dysmorphisms
Coarse thick hair
Flat nose bridge
Short nose
Prominent forehead
Possible initial symptoms
during infancy (0 - 24 months)
Signs and Symptoms
• Signs and symptoms not apparent at
birth
• Skeletal deformities; pectus carinatum,
genu valgus, kyphoscoliosis
• Waddling gait with a tendency to fall
• Delayed onset of standing and walking
• Growth delay
• Large head circumference
INITIAL SYMPTOMS (n=259)
Others
5.4
Wrists
15.4
Hips
12.7
Incresased Cranial Circumference
10.4
12.4
Chronic Ear Infections
17.4
Corneal Clouding
15.4
Knees Slightly Bent
6.6
Lower Leg Pain
Restriction of Efficient Breathing
13.9
Hearing Loss
15.4
Cervical Spine
19.7
Difficulty of Joint Movement
26.6
45.9
Abnormal Gait
48.6
Kyphosis
54.1
Growth Retardation
64.1
Bone Deformity
0.0
10.0
International Morquio Registry (2005)
20.0
30.0
40.0
Percentage (%)
50.0
60.0
70.0
Possible current symptoms
from early childhood to adolescence
Signs and Symptoms
•
Skeletal deformities; pectus carinatum, genu valgus, kyphoscoliosis, coxa
valga, hip and knee pain
•
Cervical spine instability
•
Cervical myelopathy (spinal cord compression)
•
Abnormal gait with a tendency to fall
•
Growth retardation with short trunk and neck
•
Restriction of efficient breathing
•
Fine corneal clouding
•
Hypermobile joints
•
Limited endurance
•
Coarse facial features
•
Hearing loss
•
Hepatomegaly
•
Abnormally thin enamel and frequent caries formation
•
Recurrent infection; chronic otitis, upper respiratory infection
CURRENT SYMPTOMS
(n=263; Average, 16 years)
27.4
Snoring
21.3
Recurrent Infection
10.3
Vomiting
38.4
Eye promblem
29.7
Teeth Problem
16.0
Heart Disease
Restriction of Efficient Breathing
25.5
12.5
Hernia
14.4
Liver Enlargement
Hearing Loss
29.7
Cervical Spine Instability
36.5
Difficulty of Joint Movement
61.6
Abnormal Gait
58.6
Kyphosis
52.9
Growth Retardation
87.8
Bone Deformity
91.6
0.0
10.0
20.0
30.0
40.0
50.0
60.0
Percentage (%)
International Morquio Registry (2005)
70.0
80.0
90.0
100.0
Possible clinical symptoms
from adolescence to adulthood
Signs and Symptoms
•
Skeletal deformities; pectus carinatum, genu valgus,
kyphoscoliosis, gibbus, coxa valga, hip and knee pain
•
Inability of walking (wheel-chaired)
•
Growth retardation with short trunk and neck
•
Hypermobile joints
•
Cervical spinal myelopathy
•
Restriction of efficient breathing
•
Fine corneal clouding
•
Aortic/mitral valve disease
•
Limited endurance
•
Coarse facial features
•
Hearing loss
•
Abnormally thin enamel and frequent caries formation
•
Recurrent infection; chronic otitis, upper respiratory infection
Surgical operation
(total number = 156, average; 17.5 years)
No (22%)
Yes (78%)
International Morquio Registry (2005)
Location of surgical operations
(number; 156 patients)
BMT
Hernia
Adenoid
Tonsil
Leg
Hip
Ear tube
Knee
Neck
0
10
20
30
40
50
60 Number
International Morquio Registry (2005)
MPS IVA
Clinical presentation
in MPS IVA
Organ specific
Multi-systemic manifestations
•
•
•
•
•
•
•
•
•
Atlantoaxial instability
Cervical myelopathy
Ears/Nose/Throat
Eye
Dental
Cardiovascular
Gastrointestinal
Airway disease
Skeletal/joints
Spinal cord pathophysiology
GAG (KS)
accumulation.
Metaphyseal and
epiphyseal bone
dysplasia
Degradation of
connective tissues
near the joint
Cervical myelopathy - bowel and
bladder dysfunction, decreased
endurance, apnea, hyperreflexia,
and clonus
Consequential quadriparesis or
even death
Odontoid
hypoplasia
Ligamentous
laxity
Anterior
extradural GAG
deposition
Atlantoaxial
subluxation
Spinal cord
compression
MRI (magnetic resonance imaging)
4 year-old patient
Spinal cord compression
Hypoplasia of odontoid process
Normal
CT scan (Computer tomography)
Sagittal
Coronal
Absence of odontoid process
MPS IVA patient (6.6 years )
X-ray picture on the neck
Extension
Flexion
Atlantoaxialsubluxation
Hypoplasia of odontoid
2.3 years
Ears, Nose, and Throat
•
•
•
•
•
•
•
Chronic recurrent ENT
infections
Thick and copious
secretions
Loud breathing, sleep
apnea
Hearing loss
Flattened nose bridge
Enlarged tonsils and
adenoids,
narrowed trachea,
thickened vocal cords
Large tongue
Ear problem
Mild to moderate
conductive deafness,
sensorineural deafness,
mixed deafness, especially
of higher frequencies:
mostly by the end of the
first decade
Semicircular Canals (3)
Stirrup
Anvil
Nerves
Hammer
Pinna
•
Cochlea
•
Resulting from frequent
ear infections, inner ear
and middle ear
abnormalities
Eardrum
Connects
to the nose
Eustachian Tube
Outer Ear Canal
conductive
sensorineural
Hearing loss – pathophysiology
GAG storage
Mucosal
linings
Connective
tissue
Cartilage
and bone
Recurrent loops,
leading to
progression of
symptoms
Hearing loss
Airway
narrowing
Thick and
copious
secretions
Chronic
middle ear
infections
Abnormalities or
damage in the
inner ear
Deformity of the
ossicles (middle
ear)
Eye problem
• Fine stromal corneal clouding
• Photophobia
• Strabismus
24 year-old patient
• Impaired visual field
Ciliary body
• Decreased visual acuity
Optic Nerve
• Cataracts in adulthood
Cornea
Retina
• Blindness in adulthood (rare)
• Glaucoma in adulthood (rare)
Lens
• Retinal degeneration in adulthood
Macula
Iris
(rare)
Zonules
Corneal clouding-pathophysiology
GAG storage
Non-uniform fibril
diameter
Stroma in
cornea
Increased light
scattering:
corneal clouding
Increased fibril
number density
Inhomogeneities
such as expanded
cells and collagenfree lakes in stroma
Normal
Ed
St
Ep
Affected
Dental problem
Defective thin enamel of
baby & permanent teeth
with sharp pointed cusps
Small and widely spaced
teeth
Spade-shaped incisors
Concave buccal and occlusal
surfaces and pitting
Tendency to fracture and
flake off
Frequent caries formation
39 year-old patient
Enamel
Crown
Dentine
Pulp Chamber
Cementum
Root Canal
Root
Periodontal Ligament
End of root
Nerves & Blood
Vessels
Bone
X-ray
widely spaced teeth and spade-shaped incisors :
24 year-old patient
Normal
MPS IVA
Spade-shaped
incisors
Concave occlusal
surfaces
Cardiovascular disease
Signs and symptoms
•
Superior Vena Cava
Aorta
Pulmonary
Artery
Pulmonary
vein
Left
Atrium
Mitral
valve
Right Atrium
•
Aortic
Valve
Triscupid
Valve
Pulmonary
Valve
Right Atrium
Inferior Vena Cava
•
Left
Ventricle
•
•
•
Valvular thickening /deformity
leading to insufficiency:
─ Aortic, mitral or other regurgitation
─ Mitral or other narrowing
─ Heart murmur
Congestive heart failure
Pulmonary hypertension (rare)
Coronary artery disease (rare)
Myocardial infarction (rare)
Cardiomyopathy (rare)
Generally, mild heart disease!
Heart valve - pathology
Affected
Storage material
Wild-type
Gastrointestinal tract
Mild hepatosplenomegaly, caused by excessive
storage in liver and spleen, leading to:
Hernias
Loose stools, diarrhea, constipation, abdominal
pain
Episodic, chronic
Unknown etiology, may be connected with cervical
myelopathy
Generally, mild gastrointestinal disease!
Airway problem
The most important and difficult aspect in MPS IVA is the
management of restrictive lung disease and obstructive
airway!
Frequent respiratory infections
Limited endurance
Superficial and rapid breathing
Snoring
Abnormally shaped thoracic cage: restrictive
Respiratory collapse
Airway – pathophysiology
Recurrent
loop
GAG storage
Mucosal
membrane
Connective
tissue
Cartilage
and bone
Large tongue
Adenoid, tonsil,
and vocal cord
hypertrophy
Obstructive
Airway
narrowing
Thick and
copious
secretions
Tracheobronchial
abnormalities, short
neck, large mandible
Sleep apnea
Restrictive
Noisy breathing
Shortness of breath
Chronic
respiratory
infections
Airway problem
•
•
Obstructive airways disease
Restrictive lung disease
• Sleep apnea
•High rate of anesthesia complications
• Cor pulmonale
• Respiratory insufficiency
Need for adenoidectomy/tonsillectomy/CPAP/ Bi-PAP/ Tracheostomy.
Abnormal oar-shaped ribs,
curved clavicles and scoliosis
Pathophysiology of skeletal joint and
muscle disease
Bones
Dysostosis multiplex: all bones can be affected
Ossification centers:
abnormal modeling (delayed, incomplete)
dysplasia may induce dislocation and
osteoarthritis
Storage in growth plates: destruction of cartilage
layer
Joints
GAG storage in and around (potentially all) joints
and ligaments: hyperlaxity
Joint problem
Ligamentous laxity unlike other MPS
Small joints, most severely, the wrists
with a very weak grip
Difficulties with dressing, personal
hygiene, and writing
Subluxation in neck and hip joints
Decreased joint mobility in large
joints such as hips, knees, and elbows
Range-of-motion exercises, swimming,
and computer typing appear to offer
some benefits in preserving joint
function fine motor skills and should be
started early in the clinical course.
10 year-old MPS IVA patient
Hyperlaxity of joints – pathophysiology
GAG storage
Connective
tissue
Cartilage
and bone
Degradation near the
joint
Metaphyseal
deformities, hypoplasia
of the bones,
Floppy wrists and
fingers
Knocked knee
Subluxation of hip
and neck joints
Cervical instability
Hyperlaxity
of joints
Skeletal/joint problem
10 year-old patient
Knocked knee
Floppy wrist
restriction and
contracture
Metatarsal
abnormalities
and flat foot
Sandal gap
Protrusion of
the chest and
defornity of
the ribs
Skeletal/joint problem ; 3 year-old patient (Severe)
Genu valgum
Pectus carinutum
Kyphoscoliosis
Prominent Forehead
Skeletal/joint problem ; 3 year-old patient (Severe)
Genu valgum
Pectus carinutum
Kyphoscoliosis
Prominent bone deformity
Skeletal/joint disease - Thorax
Flat, oar shaped ribs
5 year-old patient
5 year-old patient
Skeletal/joint disease - spine
Hyperkyphosis
Flared ribs
Platyspondyly
Ovoid vertebrae
Compressed vertebrae
Hyperlordosis
Anterior central
beaking
Incomplete ossification!
Skeletal/joint disease - spine
1 day
2 mo
15 mo
Beaking, Ovoid vertebrae, Gibbus, Platyspondyly
32 mo
Skeletal/joint disease - hip
8 year-old patient
Wide flared iliac
Underdeveloped
acetabula
Flattered capital femoral
epiphyses
Coxa valgus
Cartilage
Function: To decrease friction in joints
Mature articular cartilage is avascular, aneural, and
alymphatic.
Comprises:
1. Chondrocytes (5%)
2. Extracellular matrix (95%)
a. Water (75%)
b. Collagen 2 (5%)
c. Proteoglycans (20%)
d. Enzymes
e. Growth factors (PDGF, TGF beta, FGF, IGF-1)
f. Lipids
g. Adhesives (fibronectin, chondronectin)
Other bone deformities
Ulnar deviation of the wrist
Valgus deformity of the elbow
Inclinations of distal ends of radium and ulna
toward each other
Deformities of metacarpals and short
phalanges, epiphyseal deformities of the
tubular bones, widened metaphyses
Cartilage cells
New
blood
vessels
New bone
Growth Plate
Epiphyseal plate
No Vessels in Cartilage Layers!
Zones of articular cartilage and growth plate
ARTICULAR
CARTILAGE
GROWTH PLATE
RESTING
SUPERFICIAL
MATRIX
COMPARTMENTALIZATION
PROLIFERATING
Interterritorial
INTERMEDIATE
HYPERTROPHIC
Territorial
Pericellular
DEEP
TIDEMARK
CALCIFIED
CARTILAGE
BONE
BONE
Extracellular matrix of cartilage
TERRITORIAL
Collagen II/XI
INTERTERRITORIAL
Link
Protein
Biglycan
PRELP
HA
CHONDROCYTE
Collagen VI
HS-PG
Fibromodulin
Aggrecan
COMP
NC4 domain
KS
CS
Fibulin
Collagen IX
CILP
Decorin
Collagen II/XI
Integrin
Collagen II/XI
Chondroadherin
CILP: cartilage intermediate layer protein
COMP: cartilage oligomeric matrix protein
CS: chondroitin sulfate
HA: hyaluronic acid
HS-PG: heparan sulfate-proteoglycan
KS: keratan sulfate
PRELP: proline/arginine-rich end
leucine-rich repeat protein
Skeletal/joint disease - Long bones
10 year-old patient
–
–
–
Tilted radial epiphysis
Abnormal curvature and tubulation of the radial
bone
Bones are osteopenic with cortical thinning
Skeletal/joint disease – Hands
Signs, symptoms
• Tapering of the proximal
portion of metacarpals
•Small irregular carpal bones
• Distal portion of the radius
tilted toward the ulna (both
bones laterally bowed)
6 year-old patient
• Joint laxity
• Significant loss of mobility
Floppy hand deformity in a 24 year-old patient
Growth
At birth, the length and weight are within normal
ranges.
Patients grow normally at first but growth may
start to slow down around 18 to 24 months.
Those who are severely affected stop growing very
early between 4 and 8 years old.
The average final height is 127 cm for male
patients and 117 cm for female patients in the
registry from International Morquio
Organization.
Patients with an attenuated type continue to
growing into their teens and reach over 150 cm.
Bone pathology in MPS IVA mouse
B
A
Storage in cartilage cells
Growth Plate
C
Bone marrow
cortical bone
osteoblasts
sinus lining cells
D
Storage in the ligament
Weight and height at birth
BIRTH WEIGHT (n=237) Average=3.5 Kg ,
1SD=0.64
BIRTH HEIGHT (n=201) Average=52 cm ,
1SD=4.5
6
70
60
5
50
4
3
Height (cm)
Weight (kg)
40
30
20
2
10
1
0
0
International Morquio Registry (2005)
Growth Curve in MPS IVA
Girls Growth Curve (cm)
Average:117.3 cm SD: 20.9 (over 18 years)
Boys Growth Curve (cm)
Average:127.6 cm SD: 22.6 (over 18 years)
190
200
Mean
180
190
180
170
-1SD
-2SD
-3SD
160
150
170
160
150
140
Height (cm)
140
130
HGC
120
130
120
110
110
100
100
90
90
80
80
70
70
60
60
50
50
0
2
4
6
8
10
Age (years)
12
14
16
18
20
0
2
4
6
8
10
12
AGE (YEARS)
14
16
18
20
Weight Curve in MPS IVA
Boys Weight Curve (kg)
Average: 46.7 kg, SD: 18.6 (over 18 years)
Girls Weight Curve (kg)
Average: 37.1kg, SD: 14.3(over 18 years)
90
90
80
80
70
70
Mean
60
-1SD
-2SD
-3SD
50
40
30
Weight (kg)
Weight (kg)
60
50
40
30
HGC
20
10
20
10
0
0
2
4
6
8
10
Age(yrs)
12
14
16
18
20
0
1
3
5
7
9
11
Age (yrs)
13
15
17
19
MPS IVA
Genetics of MPS IVA
(Morquio A Disease)
Genetics of MPS IVA
(Morquio A Disease)
1. Why does Morquio A Disease
Occur?
Why does Morquio A Disease Occur?
Each cell contains
instructions that tell
our bodies how to
function and grow
These instructions are
contained in DNA
DNA is organized
into units called
chromosomes in
nucleus
Nucleus
Chromosomal material (chromatin) made
of DNA strands
Why does Morquio A Disease Occur?
MPS IVA is inherited
People inherited two copies of everyone gene – one
from each parent. Genes contain information
about our genetic makeup – for example, physical
characteristics such as eye color and height. All
genes that an individual inherits are organized on
23 pairs of chromosomes. Each chromosome
contains thousands genes.
Why does Morquio A Disease Occur?
Each cell contains 46 chromosomes,
except sperm and eggs, which contain half
that number. We all inherit one set of
chromosomes from each parent. They can
be organized into 22 pairs of numbered
chromosomes and one pair of sex
chromosomes, called X and Y. Men have
one X and one Y. Women have the same
22 pairs of numbered chromosomes as
men, plus two X chromosomes.
Why does Morquio A Disease Occur?
Every human being carries an estimated 8 to 10
genes that are mutated (“changed”). Some genes
changes do not have much impact, but other
changes may cause disease in the affected
individuals. Just like normal genes, mutated genes
are passed from one generation to another.
The genes for production of the enzyme N-acetylgalactosamine-6-sulfatase (GALNS) are passed
from parent to child. In MPS IVA disease, the
blueprint for this enzyme is defective; thus, the
GALNS is unable to function normally.
Why does Morquio A Disease Occur?
• The gene that makes GALNS
is found on the chromosome
16
• MPS IVA disease is an
autosomal recessive disorder;
“recessive” indicates that in
order to develop the disease,
an individual must inherit
two mutated copies of the
gene, one from each parent.
• If she or he has one faulty
gene, there is a second gene
that may produce 50% of the
normal amount of GALNS
Chromosome 16 –
mutated GALNS
gene
Chromosome 16 –
mutated GALNS
gene
Chromosome 16 –
mutated GALNS
gene
Chromosome 16
with normal gene
Why does Morquio A Disease Occur?
Males and females share the risk
Copies of the gene for GALNS are carried on
chromosome 16 that not involved in determining
an individual’s sex. Humans normally have 46
chromosomes, including the two that determine
gender (either 2 “X” chromosomes in females, or
one “X” and one “Y” chromosomes in males). The
other 22 pairs of chromosomes are called
autosomes. The gene for GALNS enzyme is
carried on one of the autosomal chromosome pairs.
Thus, MPS IVA disease is an autosomal recessive
disorder; “recessive” indicates that in order to
develop the disease, an individual must inherit two
mutated copies of the gene, one from each parent.
Genetics of MPS IVA
(Morquio A Disease)
2. Inheriting Morquio A Disease
Who is a MPS IVA carrier?
A person with just one defective gene and one normal gene for
GALNS is a carrier of MPS IVA disease. Carriers do not
develop the disease because one of the two genes for
GALNS is normal, so enough enzyme is produced to prevent
GALNS from accumulating. Although MPS IVA carriers
will not have symptoms of the disease, the odds are 50:50
that the “MPS IVA gene” will be passed on to each of their
children.
Inheriting Morquio A Disease
Normal
When both parents have
normal genes for GALNS,
their children inherit two
normal genes, one from
each parent.
If both parents have MPS
IVA disease, all of their
children inherit the two
“MPS IVA gene” and
therefore the disease.
Normal
** **
** ** ** **
Normal
Normal
MPS IVA
Normal
Normal
MPS IVA
** **
** ** **
MPS IVA
MPS IVA
MPS IVA
**
MPS IVA
Inheriting Morquio A Disease
Normal
A child with only one parent
who is a carrier has a 50%
chance becoming a carrier.
If both parents are carriers of
MPS IVA disease, with each
pregnancy there is a 50%
chance the child will inherit
one MPS IVA gene from
each parent and be a carrier,
or a 25% risk of actually
having MPS IVA disease.
That means, with each
pregnancy, carrier parents
have a 3 in 4 (75%) chance of
having an unaffected child.
Carrier
** **
** ** ** **
Normal
Carrier
Carrier
Normal
Carrier
Carrier
** **
** ** ** **
Normal
Carrier
MPS IVA
Carrier
Inheriting Morquio A Disease
If only one parent has MPS IVA and
other parent neither has the disease nor
is a carrier, all children will inherit the
MPS IVA gene from the parent with the
disorder and become carriers. None of
the children, however, will have the
disease.
If one parent has MPS IVA and the
other parent is a MPS IVA carrier,
there is a 50% chance of having a child
who inherits “MPS IVA gene” from
each parent and thus has the disease.
There is also a 50% chance of having a
child who inherits the “MPS IVA gene”
from one parent only, and becomes a
carrier.
Normal
MPS IVA
**
**
** **
**
**
Carrier
Carrier
Carrier
Carrier
Carrier
MPS IVA
** **
** **
MPS IVA
MPS IVA
**
**
Carrier
Carrier
Inheriting Morquio A Disease
For each pregnancy, the odds of
inheriting MPS IVA disease are totally
independent of whether or not a previous
child has the disease. Having one child
with MPS IVA disease does not mean
that the next child cannot inherit the
disease. Likewise, it also not mean that
the next child will have the disease.
MPS IVA
Diagnosis and
misdiagnosis
Diagnosis
Symptoms cause suspicion of MPS IVA
Genotyping
Test urinary GAG and KS levels & pattern
Normal levels
& pattern
Confirmed
diagnosis
of MPS IVA
Elevated levels
Abnormal pattern
Low activity (≤ 5%)
Perform enzyme testing
Keep the difference in urinary GAG and KS
levels between children and adults in mind!!
Normal or Other MPS?
Clinical tests
1. A full skeletal survey by radiographic studies
a. X-rays: standing anteroposterior (AP) and lateral views of flexion
and extension radiographs of the cervical spine and the odontoid
process, the chest, entire spine, pelvis view with visualization of
the femoral heads articulating with the acetabulum, the lower
extremities including the entire femur, articulation with tibia, and
ankles, AP views of both hands, forearms, elbows in extension,
humerus, and shoulder.
b. MRI of the brain stem and cervical: evaluation of odontoid
hypoplasia and cord compression.
3. Ophthalmology examination with slit lamp
4. Hearing assessment
5. Echocardiogram
6. Lab tests: urine GAG, blood and urine KS, enzyme assay, and
DNA test
7. Growth chart
Urinary GAG and KS testing
Qualitative and quantitative analysis
10 ml of morning portion of urine should be
collected in a polypropylene tube
Sample can be kept at room temperature if
analyzed within 24 hours
If the sample will not be analyzed within 24
hours, the sample should be frozen at -20°C
Sample can be sipped at an ambient
temperature.
Assay for blood and urine KS
Sandwich ELISA
This method are based on a sandwich
immunoassay method using monoclonal
antibodies specific for GAGs and to permit
measurement specific GAGs in body fluids,
culture medium, and extract from tissue.
Methods to measure KS
Sandwich ELISA Assay for Quantitation of KS
Materials
Standards ( CS of Shark cartilage )
Primary Antibody coating the plate: monoclonal anti- KS Ab
Samples: Blood or urine containing specific GAG
Secondary Antibody: Biotinylated anti-KS conjugate with
Streptavidin-Horse Radish Peroxidase
Substrate: Tetramethylbenzidine (TMB)
Sandwich ELISA
TMB
Conjugated
streptavidin
peroxidase
Biotinylated
Anti KS ab
GAGs
Anti KS ab
READ AT 450-650 nm
Urinary GAG and KS in MPS IVA with age
Attenuated
Severe
Control
10000
100
1000
10
KS (mg/gCre)
Total GAG (mg/g Cre)
Control
100
0.1
1
0.01
10
20
30
Age (years)
Left Panel: GAG
40
50
60
Severe
1
10
0
Attenuated
0
20
40
Age (years)
Right Panel: KS
60
80
Blood KS with age in MPS IVA
Control
Attenuated
Severe
1600
1400
1. Age-dependency
1200
2. Correlation between
Phenotype and KS level
KS (ng/ml)
1000
800
600
400
200
0
0
20
40
Age (years)
60
80
Testing for Morquio A Disease
Testing for Morquio A Disease
Is there a test to determine MPS IVA disease inheritance?
Because MPS IVA disease is a genetic disorder, all close
relatives of people with MPS IVA disease are at risk of
having the disease, or are potential carriers of the “MPS IVA
gene”. Families with a history of MPS IVA disease may
want to discuss the possibility of a genetic testing with their
physicians. A blood test (enzyme assay and DNA test) can
determine if a person has a MPS IVA disease or is a carrier.
Prenatal testing for MPS IVA disease is also available early
in pregnancy. Genetic counseling is available to couples
who are found to be carriers or who have a family history of
MPS IVA disease.
Testing for Morquio A Disease
Morquio A disease can be
diagnosed if there is little or no
GALNS in the blood (enzyme
assay and DNA test)
Carriers can have nearly
normal IDS levels and still
carry the faulty gene
For a precise carrier diagnosis,
a genetic test that analyzes
DNA is needed for diagnosis
Affected: blood test
(enzyme assay and
DNA test)
Carrier: Genetic test that
analyzes DNA
Testing for Morquio A Disease
Test results can:
Confirm or rule out the presence of the
faulty gene
Relieve uncertainty
Enable informed decision-making
regarding medical care
Help other family members understand
their risks
Testing for Morquio A Disease
Psychological considerations:
• Depression or despair may occur after a positive test
• Changes in family dynamics may also occur
− Anger over a positive test
− Guilt over escaping a disease that affects other
family members
Enzyme activity
N-acetylgalactosamine 6-sulfatase activity
in patients ranges from 0 - 5% of normal
Measurement of blood KS and
enzyme activity
Whole blood sample
Fill an EDTA tube with 8 ml blood (4 ml in children)
Sample should be kept at room temperature
Needs to arrive at the lab for analysis within 24 hours
Leukocyte sample
Spin blood at 3000 rpm
Store plasma at -20°C to -80°C
Isolate leukocytes from the pellet
The dry leukocyte pellet can be stored at -80°C until
shipment
Leukocytes and plasma sample should be sent together
for analysis
Genotyping
Testing
Fill an EDTA tube with the patients blood (5
ml)
Keep samples at room temperature
Samples should arrive at a lab for analysis
within 48-72 hours
Summary of Mutations
To date, about 130 different mutations and seven
polymorphisms causing an amino acid change
Genotype/phenotype correlation for some of these
mutations
GALNS structural modeling: Severe mutations
located at the core of the structure leading to
destruction of the hydrophobic domain, modification
of the packing, or modification of the active site, and
attenuated mutations located on the surface of the
GALNS protein
Common mutations in Irish (pI113F, pT312S),
Italian (pM1V, pW10X), Japanese (pN204K, double
gene deletion), and pan-ethnic (pR386C)
A large proportion (over 70%) of known lesions by
missense mutations
Incidence of Frequent Mutation
(Individual Mutation n=314)
4 times
13%
3 times
11%
2 times
18%
single
21%
R386C
8%
I113F
7%
G301C
7%
M1V
3% T312S
2%
A291T*
2%
Double gene
deletion
2%
M391V
2%
W10X
P125L* 2%
2%
Variety of Mutation (n=129)
large
Splicing rearrange
ments
Insertion 7%
2%
1%
deletion
9%
nonsense
6%
Others
2%
missense
73%
a.
1
2
F1
3
4
5
F2
6
7
8
9
10 11 12
F4
F3
13
14
F5
b.
M1 F1 F2 F3 F4 F5 M2 C
Fragment
Primer names
Size
GMO75/ GMO11R
0.3 kb
F2 (exons 22-4)
GMO4/GMO5R
2.0 kb
F3 (exons 55-9)
GMO13/GMO7R
5.8 kb
F4 (exons10(exons10-12)
MO25/GMO9R
5.0 kb
F5 (exons 1313-14)
GMO10/TOMF14R
3.7 kb
3.0 kb F1 (exon 1)
1.0 kb
500 bp
Misdiagnoses
Other bone dysplasias
Other MPSs
Obstructive airways disease
MPS IVA
Management and
treatment
General management issues
Inter- and multidisciplinary input
necessary
Centers of expertise exist in most countries
Regular monitoring and evaluation
advised
No “one-size-fits-all” approach available
Special care around anaesthetic
procedures
Special orthopaedic and respiratory care
Treatment options
Bone Marrow Transplant/ Hematopoetic
Stem Cell Transplantation
(BMT/HSCT); limited effectiveness
Palliative Care; orthopedic surgeries
Physiotherapy
Enzyme Replacement Therapy (ERT);
under development
Current status of ERT on MPS
Type
MPS I
Status
Approved
Company
Genzyme/BioMarin
BMT
+
MPS II
MPS IIIA
MPS IIIB
Phase III
Preclinical
Preclinical
TKT/Genzyme
TKT
TKT
+/No
No
MPS IIIC
MPS IVA
MPS IVB
MPS VI
MPS VII
NA
Preclinical
Preclinical
Approved
Preclinical
?
Inotech
?
BioMarin
BioMarin
No
+/NA
+
+
Treatment and management
Cervical cord compression: Surgery to
decompress compression and stabilize the
upper cervical spine, usually by, can be
lifesaving.
Corneal clouding: corneal transplantation - not
always successful
Deafness: Ventilating tubes minimize episodes
of acute otitis media and chronic middle ear
effusions
Treatment and management
Joint laxity: physical therapy, bracing
Airway disease (obstructive and restrictive):
Obstructive Airway Disease. A narrowed trachea,
thickened vocal cords, redundant tissue, and an
enlarged tongue all contribute to airway obstruction.
Sleep apnea - Loud snoring and daytime sleepiness.
a. Tracheostomy
b. High pressure nasal continuous positive airway
pressure and supplemental oxygen
c. Tonsillectomy and adenoidectomy
Cervical cord compression
Cervical decompression or fusion surgery is recommended if
there is some evidence for instability or compression at any
age (generally, it may happen after 4 years). Prophylactic
fusion surgery is controversial without a proof of spinal cord
compression.
C1-C2 fusion (or if necessary, posterior occipito-cervical
fusion) in asymptomatic or mild symptomatic patients
Posterior occipito-cervical fusion with anterior decompression
in symptomatic patients with a severe compression
Complications: instability below the level of the fused segment
and thoracic spinal cord compression
After operation of cervical fusion
5 year-old patient
Anesthesia
Patients with MPS IVA: major anesthesia risks.
Risk factors: chest wall deformities, hypoplasia of
odontoid process, anterior dislocation of the vertebral
axis with resultant spinal cord compression.
Manual in-line stabilization of the head and neck:
difficult direct laryngoscopic intubation because of
inability to maintain an adequate airway and limitation
of visualization during intubation.
Angulated video-intubation laryngoscope (AVIL): a new
helpful device to aid endotracheal intubation in patients
when cervical spine immobilization impairs direct
laryngoscopy.
Recovery from anesthesia: slow and postoperative
airway obstruction in common.
Death: reported as a result of anesthesia complication.
BMT/HSCT
Performed in children with MPS IVA
Outcomes improved: joint mobility
Bone disease is usually not beneficially affected
and requires careful orthopedic management
May get some growth unless the patient stop
growing
The detailed assessment is still required for a
long-term effectiveness.
MPS IVA – specific follow-up
assessments
At least annually:
GALNS level, urinary GAGs, urinary and blood KS,
health assessment questionnaire
ENT exam and audiology
Eyes – vision, pressure, split lamp, fundoscopy, ERG for
suspected retinal disease
Respiratory function: FVC/FEV +/- sleep study
Skeletal survey - hips, spine, knees (pediatric patients)
MRI – neck (pediatric patients)
Every other year:
Heart: ultrasound and ECG
Spleen and liver volume
MPS IVA Registry
Help to increase disease awareness, and enhance the
understanding of the variability, progression, and
natural history of MPS IV.
Evaluate the long-term effectiveness and safety of
available treatment options.
Provide patient reports to help physicians assess
value of therapeutic interventions in individuals.
Generate reports on aggregate patient data to help
develop guidelines for monitoring and managing of
patients.
Identifying patients at
an early stage
Educating peers
Good education to
families, doctors, and
local community
Quality of life in each
patient will be better.
Supporting families
Treating patients in an
early stage and
in a proper manner